The Program Project hypothesizes that the processes of progenitor proliferation, neural differentiation, axon extension and synapse formation are regulated by neuron-neuron and neuron-glial interactions. These cell-cell interactions, in turn, are mediated through the actions of multiple intercellular and intracellular signals that impact seemingly unrelated developmental events. Our studies will elucidate molecules and mechanisms that regulate proliferation, survival, differentiation and synaptogenesis in the developing brain. They focus on the roles of BDNF and Eph family members and lead us to increased understanding of how to effect brain repair and regeneration. Importantly, the studies move from the culture dish, to the developing brain in vivo. Moreover, they extend the work to analysis of a neurotherapeutic molecule used for women of child bearing age and young children. To achieve our goals, Project 1 will examine mechanisms by which the anticonvulsant, valproic acid affects development of neurons and glia, ranging from proliferation control to differentiation and release of BDNF from neurons and glia. Project 2 will explore an emerging field of signal interaction between Eph and Trk family receptors. Project 3 will define mechanisms underlying synaptic plasticity by examining the roles of cytoskeletal structures in transmitter receptor trafficking and spine enlargement/formation and shrinkage and their regulation by intracellular kinases and BDNF. Project 4 will explore mechanisms underlying the processing and release of pro- and mature isoforms of BDNF from neurons. Project 5 will examine mechanisms underlying astrocyte-neuron interaction mediated by the release and synthesis of BDNF. In sum, these interactive projects are designed to explore roles of BDNF in development and disease. Understanding the mechanisms underlying these processes may provide insights into therapeutic interventions that will impact diseases of the developing brain.